CS217952B2 - Method of making the new derivatives of the chnazoline - Google Patents

Description

The invention relates to novel quinazoline derivatives and processes for their preparation.

In particular, the invention relates to novel quinazoline derivatives of the general formula I,

where it represents

R is a (C 2 -C 3) haloalkyl group

R1 and R2 are each hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, nitro, trifluoromethyl,

R3 is a group of formula

where R 1 represents a hydrogen atom, a halogen atom,

W is an oxygen or sulfur atom, and methods of making the same.

The term "C 2 -C 3 polyhaloalkyl", represented by R in formula I, represents an alkyl group having 2 to 3 carbon atoms substituted by one or more halogen atoms, and preferably includes radicals such as 2,2-difluoroethyl - 2,2 2,2-trifluoroethyl-,

2.2.2-Trlloroethyl-, 2-bromo-2,2-difluoroethyl-, 2-chloro-2,2-difluoroethyl-, trifluoromethyl-, 2,2,3.3-tetrafluoropropyl- and 2,2,3,3,3 pentafluoropropyl, and the like. The term "alkyl" refers to both straight and branched chain aliphatic hydrocarbon radicals. Examples of such radicals include methyl, ethyl, n-propyl and isopropyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy. The term "halogen" refers to all halogens, with fluorine, chlorine and bromine being preferred.

The quinazoline derivatives of formula (I) are novel and have excellent anti-inflammatory and analgesic activity at very low toxicity.

217932

For example, 1- (2,2,2-trifluoroethyl) -3-phenyl-6-chloro-2 '(1H) quinazolinone has a marked inhibitory effect on edema induced by carragenine in rats, with no toxic symptoms observed. mg / / kg was not observed in the faeces for internal bleeding The anti-inflammatory effect of this compound is much more pronounced than that of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine (phenylbutazone) and acute, subacute and chronic toxicity is much lower compared to phenylbutazone.

The invention relates to novel and useful quinazoline derivatives having excellent pharmacological properties.

The object of the invention is a process for the production of these valuable compounds which can be used on an industrial scale.

Further details of the invention are apparent from the following description.

and

The compounds of the invention are prepared by the compound of formula (V):

where

R, R 1, R 2 and R 5 are as defined above and

Compound

X is an oxygen atom or an imino group, reacted with a compound containing an NCO or NCS group in the molecule, such as a carbamic acid ester or a carbamic acid halide, an acid, anate or a salt thereof, a thiocyanic acid or a salt thereof.

The reaction may be carried out by reacting a compound of formula V with a carbamic ester or carbamic halide in the presence of a Lewis acid such as zinc halide, or cyanate or sele or thiocyanic acid or a salt thereof. presence of a solvent such as acetic acid.

Examples of carbamic acid esters include methyl carbamate, ethyl carbamate, isopropyl carbamate and benzyl carbamate.

Examples of carbamic acid halides are carbamoyl chloride.

Examples of cyanate salts are sodium cyanate and potassium cyanate.

Salts of thiocyanic acid include sodium thiocyanate, potassium thiocyanate and ammonium thiocyanate.

The reaction temperature may vary depending on the particular compound containing the NCO or NCS group used.

The pharmacological activity of the compounds prepared by the process of the invention results from the following data:

Dose mg / kg Inhibition of edema

Compounds of the Invention 1- (2 ‘, 2‘, 2‘-Trifluoroethyl) -4-phenyl-6-chloro-2- (1 H) -quinazolinone

1- (2‘, 2‘, 2‘-Trifluoroethyl) -4-phenyl-21 (1H) -quinazolinone

1- (2‘, 2‘, 2‘-Trifluoroethyl) -4-phenyl-6-methoxy-2- (1H) -quinazobnon

1- (2 ‘, 2‘, 2‘-Trifluoroethyl) -4-phenyl-6-nitro-2 (1H) -quinazclinone

1- (2 ‘, 2‘, 2‘-Trifluoroethyl) -4- (o-fluorophenyl) -6-chloro-2- (1H) -quinazolinone

1- (2-Chloro-2,2-difluoroethyl) -4-phenyl-6-methoxy-2 (1H) -quinazolinone

1- (2,2,3,3, -Tetrafluoropropyl) -4-phenyl-6-methoxy-2H (1H) -quinazolinone

1- (2,2,2-Trifluoroethyl) -4-phenyl-S-indethoxy-2 (1H) -quinazolinone

50 37.1 109 46.4 200 53.7 50 44.4 100 ALIGN! 50.6 200 61.7 50 39 0 100 ALIGN! 51.0 200 60.0 50 48.2 100 ALIGN! 53.1 200 64.6 50 39.5 100 ALIGN! 45.5 200 51.3 50 35.3 100 ALIGN! 49.0 50 33.3 100 ALIGN! 5i3, l 50 42.0 100 ALIGN! 61.9

Compound

Dose mg / kg

Inhibition of Smoke

Known compounds

1-Methyl-4-phenyl-6-chloro-2- 50 32.1 (1H) -quinazolinone 100 ALIGN! 35.1 200 43.0 1-Ethyl-4-phenyl-6-chloro-2 '(1 H) - 50 29.3 -quinazolinone 100 ALIGN! 38.6 1- (2‘-Chloroethyl) -4-phenyl 1-6- 50 - -nitro-2 (1H) quinazolinone 100 ALIGN! 14.4 200 23.9 1- (2‘-Ethoxyethyl) -4-phenyl- 50 - 6-nitro-2 (1H) -quinazolinone 100 ALIGN! 26.6 200 43.6 1-Ethyl-4- (2'-thienyl) -4-chloro- 50 20.7 -2 (1H) -quinazolinone 100 ALIGN! 30.0 200 38.7

The invention is illustrated in more detail in the following examples, where preferred conditions are used. The examples are for illustrative purposes only, but do not limit the scope of the invention in any way.

Example 1

A mixture of 62.7 g of 2- (2,2,2-trifluoroethylamino) -5-chlorobenzophenone, 107 g of ethyl carbamate and 10 g of zinc chloride was heated to 190 ° C (oil bath temperature) for three hours. The chloroform solution was washed successively with dilute hydrochloric acid and water and then dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the remaining solid was washed three times with 100 ml of isopropyl ether and dried. with 49.5 g of 1- (2,2,2-trifluoroethyl) -4-phenyl-6-chloro-2- (1H-quinazoline) as a light gray powder, which was recrystallized from ethanol to give pale yellow needles, m.p. 186.5-187.5 ° C.

The following compounds are obtained in an analogous manner:

1- (2,2,2-triifluoroethyl) -4-phenyl-6-methyl-2 (1H) -quinazolinone, mp 178.0-179.0 ° C; Ir (2,2,2-trifluoroethyl) -4-phenyl-6-trifluoromethyl-2H (1'H) -quinazolinone, m.p.

174.0 ° C;

1- (2,2,2-trifluoroethyl) -4-phenyl-6-bromo-2H (1H) -quinazolinone, mp 199.0 - 200.0 ° C;

1- (2,2,2-trifluoroethyl) -4-cyclohexyl-6'-chloro-2 (1H) -quinazolinone, mp 180.0-181.0 ° C;

1- (2,2,2-trifluoroethyl) -4- (2-thienyl) -6-methoxy-2H (1H) -quinazolinone, m.p.

158.0 ° C;

1- (2,2'-difluoroethyl) -4-phenyl-6-nitro-2H (1H) -quinazolinone, mp 196.0-197.0 ° C; 1- (2-Chloro-2,2-difluoroethyl) -4-phenyl-6-methoxy-2H (1 H) -quinazolinone, m.p.

155.0 ° C;

1- (2,2,3,3,3-pentafluoropropyl) -4-phenyl-6-methoxy-2 (1H-quinazolinone, mp 135.0-136.0 ° C;

1- (2,2-trifluoroethyl) -4-phenyl-2- (1H) -quinazolinone, mp 181.5-182.0 ° C;

1- (2,2,2-trifluoroethyl) -4-phenyl-6-methoxy-2 (1H) -quinazolinone, mp 157.0-156.0 ° C;

1- (2,2,2-trifluoroethyl) -4-phenyl-6-nitro-21 (1H) -quinazolinone, mp 195.0-196.0 ° C;

l- (2 _i, 2,3,3,3-pentafluoro-propyl) -4-phenyl-6-methyl-2H (lHj -quinazolinone, mp 175.5 to

176.5 ° C.

Example 2

To a solution of 1.0 g of 2- (2,2,2-trifluoroethylamino) -5-methoxybenzophenone in 15 ml of acetic acid was added 1.0 g of ammonium thiocyanate and the mixture was heated at 100 ° C for 10 hours. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated, and the residue was chromatographed on a silica gel column using chloroform as eluent to give 1- (2,2,2-trifluoroethyl). 4-phenyl-6-methoxy-2 (1H) -quinazinethione Recrystallization from chloroform-ethanol gave red-brown crystals, m.p. 194-195 ° C.

Example 3

To a mixture of 2.8 g of (2,2,2-trifluoroethylamino) benzophenoimine, 2 ml of ethyl chlorocarbamate and 20 ml of benzene was added dropwise 2.0 g of triethylamine and the mixture was refluxed for three hours. After cooling, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure. The residue was absorbed on a silica gel column and eluted with chloroform. 1- (2,2,2-Trifluoroethyl) -4-phenyl-2 (1H) -quinazolinone is obtained, which after recrystallization from ethanol gives colorless crystals of m.p. 181.5-162.0 ° C.

Claims (4)

SUBJECT What is claimed is: 1. A process for the preparation of the novel quinazoline derivatives of the general formula (I) in which: R is a C 2 -C 3 polyhaloalkyl group, R 1 and R 2 are each hydrogen or halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro or trifluoromethyl, R 3 is cyclohexyl, thienyl, or a compound of the formula wherein R 1 is hydrogen or halogen, W is an oxygen or sulfur atom, characterized in that a compound of the general formula wherein R, R1, R2 and R3 are as defined above and X represents an oxygen atom or an imino group, reacted with a compound containing a group in the molecule. = NCO- or = NCS- such as a carbamic acid ester, carbamic acid halide, cyanoic acid or its salts or thiocyanic acid or its salts. 2. Process according to claim 1, characterized in that starting compounds are used in which R represents a group of the general formula: -IGH2) _n -R ' YNÁLEZU in which R ‘denotes a trihalomethyl group, n denotes 1 or 2 and the other symbols have the meaning given above, 3. A process according to claim 2, wherein a compound of formula (Va) wherein R1, R1, R2, R3 and n are as defined above is reacted with a carbamic acid ester or a carbamic acid halide. 4. A process according to claim 1, wherein the quinazoline derivatives of the general formula wherein R1 and R2 are each hydrogen or halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro or trifluoromethyl, R3 is phenyl, halophenyl , cyclohexyl or trenyl, X 1, X 2 and X 3 are each halogen, n is an integer of 1 or 2, characterized in that a compound of the formula wherein R 1, R 2, R 3, X 1, X 2, X 3 and n are as defined above , is reacted with cyanic acid or a salt thereof or a carbamic acid ester or halide.